S264: PRELIMINARY ANALYSES OF A NON-GENE-EDITING ALLOGENTIC CAR-T IN CD19+ RELAPSED OR REFRACTORY NON-HODGIN’S LYMPHOMA
Authors: X. Wang, L. Xue, S. Li, Q. Fan, K. Liu, R. Jin, X. Yang, T. Wang, L. He, J. Li
Journal: HemaSphere (2022)

Background: A novel non-gene-editing allogeneic CAR-T platform was developed on the base of intracellular retention of membrane proteins, and named ThisCART (This = TCR and/or HLA-I intracellular sequestered). CD19-directed ThisCART (ThisCART19A) cells are readily produced with a single lentiviral vector, encoding both a CD19-targeting CAR and an anti-CD3 single chain antibody with the KDEL peptide fused to its C-termini (Figure 1). ThisCART19A cells, deficient of surface TCR/CD3 complexes in extended culture, induced no xegoneic GvHD reaction in murine model. Similar to conventional CD19-directed CAR-T, they exhibited potent CD19-specific cytotoxicities both in vitro and in vivo. Aims: To evaluate the safety, pharmacokinetics and clinical activity of ThisCART19A in patients with refractory or relapsed CD19 positive B cell malignancies. Methods: A single-center, open-label, single-arm study (NCT04384393) is ongoing to evaluate the safety, pharmacokinetics and clinical activity of ThisCART19A in patients with refractory or relapsed CD19 positive B cell malignancies, including acute or chronic lymphoblastic leukemia, non-Hodgkin’s lymphoma. Standard or enhanced lymphodepletion with fludarabine and cyclophosphamide was followed by infusion of ThisCART19A at a dose range of 0.2-60x106cells/kg. The pharmacokinetics of ThisCART19A cell was assessed by flow cytometry or quantitative PCR. Results: As of January 30th, 2022, eight evaluble subjects with aggressive or advanced non-Hodgkin’s lymphoma received ThisCART19A infusion (Table 1). Subject #3 had received two subsequent autologous CAR-T therapies and relapsed after each treatment. Adverse event profile is acceptable: no ≥3 grade of CRS or ICANS and no evidence of GvHD reaction. Two subjects experienced reversible Hemophagocytic lymphohistiocytosis with decreased lymphocytes and neutrophils. Dose-dependent CAR-T expansion was observed in six subjects pretreated with enhanced lymphodepletion. Lack of CAR-T expansion in the other two is likely due to the standard lymphodepletion or quick disease progress. PET/CT (≥28 days) scan demonstrated one partial response and five complete responses. Among these five, three remain in remission with one in continued follow-up over 8 months. Table 1 - Patient baseline characteristics. Patients No. Pt1 Pt2 Pt3 Pt4 Pt5 Pt6 Pt7 Pt8 Age/Sex 41/F 54/M 42/M 58/F 44/M 40/M 67/F 51/F Pathological type DLBCL MCL DLBCL DLBCL tFL-DLBCL FL DLBCL MZL Ann Arbor/ IPI/FLIPI IV B/4 IV A/3 IV B/3 III B/4 IV B/3 IV A/4 IV B/3 IV B/1 Since Initial Diagnosis 3 yrs 1 yr 4 yrs 1 yr 2 yrs 1 yr 1 yr 3yrs Extranodal disease Yes No Yes Yes No Yes Yes Yes Lines of prior therapies 4 4 4 5 7 5 2 3 Prior auto CAR T No No Auto CART CD19 Auto CART CD20 No No No No No R/R Refractory Refractory Relapsed Refractory Relapsed Refractory Relapsed Relapsed Best Response PR CR CR CR CR CR PD PD Image:Summary/Conclusion: ThisCART19A cells demonstrated potent CD19-dependent cytotoxicity and no xenogentic GvHD in murine models. In this preliminary analysis on evaluable lymphoma subjects, ThisCART19A exhibited an acceptable safety and an encouraging clinical response profiles, both comparable to those for marketed autologous products.